Abstract
Impulse control disorders (ICDs) are frequent non-motor symptoms in Parkinson's disease (PD), with potential negative effects on the quality of life and social functioning. ICDs are closely associated with dopaminergic therapy, and genetic polymorphisms in several neurotransmitter pathways may increase the risk of addictive behaviors in PD. However, clinical differentiation between patients at risk and patients without risk of ICDs is still troublesome. The aim of this study was to investigate if genetic polymorphisms across several neurotransmitter pathways were associated with ICD status in patients with PD. Whole-exome sequencing data were available for 119 eligible PD patients from the Norwegian ParkWest study. All participants underwent comprehensive neurological, neuropsychiatric, and neuropsychological assessments. ICDs were assessed using the self-report short form version of the Questionnaire for Impulsive-Compulsive Disorders in PD. Single-nucleotide polymorphisms (SNPs) from 17 genes were subjected to regression with elastic net penalization to identify candidate variants associated with ICDs. The area under the curve of receiver-operating characteristic curves was used to evaluate the level of ICD prediction. Among the 119 patients with PD included in the analysis, 29% met the criteria for ICD and 63% were using dopamine agonists (DAs). Eleven SNPs were associated with ICDs, and the four SNPs with the most robust performance significantly increased ICD predictability (AUC = 0.81, 95% CI 0.73-0.90) compared to clinical data alone (DA use and age; AUC = 0.65, 95% CI 0.59-0.78). The strongest predictive factors were rs5326 in DRD1, which was associated with increased odds of ICDs, and rs702764 in OPRK1, which was associated with decreased odds of ICDs. Using an advanced statistical approach, we identified SNPs in nine genes, including a novel polymorphism in DRD1, with potential application for the identification of PD patients at risk for ICDs.
Highlights
Patients with Parkinson’s disease (PD) have a threefold increased odd for developing impulse control disorders (ICDs) and related compulsive behaviors when compared to controls [1, 2]
Patients with ICD did not differ from patients without ICD in terms of sex, education, duration of PD, Mini-Mental State Examination (MMSE) scores, or scores on Unified Parkinson’s Disease Rating Scale (UPDRS) II, III, or IV, but patients with ICDs tended to be younger (p = 0.050) and scored significantly higher on Montgomery and Aasberg Depression Rating Scale (MADRS) (p = 0.010)
When controlling for dopamine agonist (DA) use and age, we identified two genes with polymorphisms that were independently associated with ICDs (Table 3). rs5326 is positioned in the 5' untranslated region (UTR) of the DRD1 gene, which encodes the dopamine receptor D1, and was associated with an increased risk of ICDs
Summary
Patients with Parkinson’s disease (PD) have a threefold increased odd for developing impulse control disorders (ICDs) and related compulsive behaviors when compared to controls [1, 2]. These behaviors are characterized by lacking control of rewarding behaviors, such as gambling, sexual activity, eating, and buying. Patients may develop a preoccupation with hobbies, punding behaviors, and an addiction-like pattern of dopaminergic medication use. Not all patients develop ICDs when exposed to dopaminergic medications, arguing that some individuals are more susceptible to DRT than others. Identified demographic-risk factors, such as familial history of addiction, increased impulsivity, and noveltyseeking traits [1, 5], argue that the individual vulnerability may be of genetic origin
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